CN102875421B - Aziridine compound loop opening method based on p-nitrobenzoic acid - Google Patents
Aziridine compound loop opening method based on p-nitrobenzoic acid Download PDFInfo
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- CN102875421B CN102875421B CN201210386433.6A CN201210386433A CN102875421B CN 102875421 B CN102875421 B CN 102875421B CN 201210386433 A CN201210386433 A CN 201210386433A CN 102875421 B CN102875421 B CN 102875421B
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- nitrogen heterocycle
- nitrobenzoic acid
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- -1 Aziridine compound Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 23
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 title claims abstract description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000012434 nucleophilic reagent Substances 0.000 claims abstract description 9
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000001294 propane Substances 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- 238000007142 ring opening reaction Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 9
- 230000004913 activation Effects 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 34
- 150000001541 aziridines Chemical class 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000001819 mass spectrum Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000001994 activation Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 1
- QUJLPICXDXFRSN-UHFFFAOYSA-N scandium;trifluoromethanesulfonic acid Chemical compound [Sc].OS(=O)(=O)C(F)(F)F QUJLPICXDXFRSN-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an aziridine compound loop opening method based on p-nitrobenzoic acid. A tosyl activated aziridine compound is taken as a starting material, an alkali metal hydroxide is taken as a catalyst, the p-nitrobenzoic acid is taken as a nucleophilic reagent in a dimethyl sulfoxide solvent system, and loop opening reaction is carried out on the aziridine compound. The aziridine compound loop opening method based on the p-nitrobenzoic acid disclosed by the invention is simple in a reaction process, conditions are mild, the loop opening method has extensive universality, the yields of aziridine compounds in different structures are higher, and the regioselectivity is higher.
Description
Technical field
The present invention relates to a kind of method of p-nitrobenzoic acid to the nitrogen heterocycle propane compound open loop of different structure of utilizing, belong to technical field of organic synthesis.
Background technology
Nitrogen heterocyclic is important building block and the intermediate in organic synthesis, is present in many natural products, has good antiviral, antitumor and other biological active.Can there are a series of important reactions in nitrogen heterocyclic, as ring-opening reaction, rearrangement reaction, reduction and elimination reaction etc.Its nucleophilic ring opening reaction can be used for synthesizing
β-the aminocompound that replaces, so synthetic many have biological activity and medication chemistry industry extremely have application prospect amino alcohol, amino acid, alkaloid and
β-the compounds such as Nei phthalein amine, also can be as part and the auxiliary in asymmetric synthesis.The ring-opening reaction method of exploring cheap, efficient nucleophilic reagent and ethylenimine is quite subject to investigator's extensive attention.
Multiple nucleophilic reagent (alcohols, amine and amides, mercaptan and thiophenols) can carry out ring-opening reaction with ethylenimine.Alcohol just has report with reacting as far back as the eighties of last century sixties of nitrogen heterocyclic, the people such as Ulrich (Ulrich H., Emanuel P., Friedrich K Z. The action of alcohols on ethylenimines (aziridines). Synthesis of β-amino ethers[J]. Chemische Berichte, 1964, 97 (2): 510-519.) used very strong Lewis acid boron trifluoride to carry out reacting of the various fatty alcohol of catalysis and ethylenimine, need to use the boron trifluoride of larger dose, reaction process is difficult to control, long reaction time, productive rate is not high yet.Amine and amides nucleophilicity are very strong, do not have under catalyst action yet can with ethylenimine synthetic 1, the 2-diamine compounds that react.The people such as Peruncheralathan (Peruncheralathan S., Henze M., Schneider C. Scandium Triflate Catalyzed Aminolysis of meso-Aziridines[J]. Synlett, 2007,2007 (14): 2289-2291.) with trifluoromethanesulfonic acid scandium, aniline is reacted with ethylenimine, within very short time, obtained very high yield, but this reaction for quilt-TS, the nitrogen heterocyclic yield of the group activations such as-COPh is not high.Mercaptan and thiophenol also can react with ethylenimine under the condition of catalyzer not having, and the corresponding alcohols of reactivity ratio is high, and this class reaction is carried out conventionally in polar solvent.Although (the Fan R. H. such as Fan, Hou X. L. Efficient ring-opening reaction of epoxides and aziridines promoted by tributylphosphine in water[J]. J. Org. Chem. 2003,68:726 – 730.) develop the nucleophilic ring opening reaction of carrying out in water, but need to add PBu
3shi Fanying just can occur, and selectivity is very low.
Containing the diethyl malonate of α-hydrogen, also can carry out nucleophilic reaction with nitrogen heterocyclic, this reaction generally need to could realize with α-hydrogen that highly basic seizes carbonyl.CN 102503861 has set forth the open-loop method of a kind of diethyl malonate to nitrogen heterocycle propane compound, and the method be take alkali as catalyzer, realizes the ring-opening reaction of diethyl malonate to nitrogen heterocycle propane compound in different solvents.This patent is the unique patent about nitrogen heterocycle propane compound open-loop method of delivering of China.
On carboxyl, the oxygen of electron rich is the avtive spot of carboxylic-acid nucleophilic reagent, also can carry out ring-opening reaction with nitrogen heterocycle propane compound, but relevant patent and document is very limited.Directly catalysis carboxylic acid was proposed (Yadav J. S. in 2002 by people such as Yadav to the method for ethylenimine ring-opening reaction, Reddy B. V. S., Sadashiv K., et al. Indium Tri ate-Catalyzed Ring Open-ing of Aziridines with Carboxylic Acids[J]. Tetrahedron Letters, 2002,43 (11): 2099-2101.), they have adopted In (OTf)
3make catalyzer, take methylene dichloride as solvent, under room temperature condition, react, yield, between 85%-92%, and has good corresponding selection, shortcoming to be catalyst I n (OTf)
3more expensive.
In sum, although the research of ethylenimine ring-opening reaction has obtained certain progress, but the weak points such as ubiquity, and catalyzer price is high, the reaction times is long, selectivity is low, find new nucleophilic reagent and ethylenimine and carry out ring-opening reaction, so that reaction is easier to operation, more environmental protection, productive rate is higher, and selectivity is worth more by force people further to go to explore and find.
Summary of the invention
The object of this invention is to provide the method for a kind of p-nitrobenzoic acid to the nitrogen heterocycle propane compound open loop of different structure.
The nitrogen heterocycle propane compound open-loop method that the present invention is based on p-nitrobenzoic acid is: the nitrogen heterocycle propane compound of the tosyl group of take activation is starting raw material; take alkali metal hydroxide as catalyzer; in dimethyl sulfoxide solvent system; use p-nitrobenzoic acid as nucleophilic reagent, nitrogen heterocycle propane compound is carried out to ring-opening reaction.
Wherein, the nitrogen heterocycle propane compound of described tosyl group activation has following general structure:
In formula, R
1represent H, C
1～C
10alkyl,
,
or
;
Wherein, described R
2represent H, methyl, methoxyl group or halogen.
Preferably, R wherein
1represent C
1～C
6alkyl,
,
or
; R
2represent H, methyl, methoxyl group or halogen.
Its concrete reaction formula is as follows:
Or the nitrogen heterocycle propane compound of described tosyl group activation has following general structure:
Wherein, n is 1～7.
Preferably, n is 3 or 4.
Its concrete reaction formula is as follows:
。
Above-mentioned reaction is carried out in dimethyl sulfoxide solvent system, and the consumption of dimethyl sulfoxide (DMSO) is 2～10mL/mmol nitrogen heterocycle propane compound.Because dimethyl sulfoxide (DMSO) has very strong water-absorbent, be exposed to the very fast moisture absorption of meeting in air, and make system with micro-moisture, therefore, further research reaction is particularly important to the tolerance of water.Use the dimethyl sulfoxide (DMSO) of new distillation to react in dry nitrogen, with the comparison of reacting without drying nitrogen protection, speed of reaction and yield all do not have significant difference, illustrate that above-mentioned reaction has good tolerance for micro-water.
The alkali metal hydroxide that is used for impelling above-mentioned reaction to carry out is LiOH, NaOH, KOH, CsOH etc., and wherein preferred alkali metal hydroxide catalyzer is KOH or CsOH.
Further, in open-loop method of the present invention, the consumption mol ratio of reaction raw materials p-nitrobenzoic acid and nitrogen heterocycle propane compound is 0.5～5 ︰ 1, and the mole number consumption of alkali metal hydroxide catalyzer is 5～40% of nitrogen heterocycle propane compound mole number.
Usually, ring-opening reaction of the present invention is carried out at 20～80 ℃, and preferred temperature of reaction is 40～60 ℃.
The present invention take that the nitrogen heterocycle propane compound of tosyl group activation is starting raw material, and tosyl group, as electron-withdrawing substituent, can reduce the cloud density on nitrogen heterocyclic, makes it easily by nucleophilic reagent attack.Tosyl group on ring-opening reaction after product adopts ordinary method to remove, and is not the emphasis that the present invention describes, therefore the present invention is not explained it.
The invention provides and a kind ofly take p-nitrobenzoic acid as nucleophilic reagent, the nitrogen heterocycle propane compound open-loop method that alkali metal hydroxide is catalyzer, the method, except simple to operate, outside reaction conditions gentleness, also has the following advantages:
1) catalyzer adopting is cheap, and catalytic activity is high, compares to In (OTf)
3catalyzer, price greatly reduces;
2) solvent dimethyl sulfoxide (DMSO) environmental friendliness, reacts particularly valuable by force to the tolerance of water;
3) open-loop method of the present invention has universality widely, and the ethylenimine of different structure all can obtain higher yield within a short period of time;
4) reaction gained open-loop products has higher regioselectivity, and when particularly on ethylenimine, substituting group is aliphatic chain, reaction table reveals extraordinary regioselectivity.
Therefore,, as a kind of open-loop method of new nitrogen heterocycle propane compound, the present invention has very strong actual application value.
Embodiment
The present invention is further detailed by following examples, but following examples can not be interpreted as to be limiting the scope of the invention.Within not departing from technical scope of the present invention, any for nonessential improvement of the present invention and variation, all should be included in technical scope of the present invention.
Embodiment 1.
Add table 1 in 50mL Erlenmeyer flask in, structural formula is as the nitrogen heterocycle propane compound 1mmol of 1a, cesium hydroxide 0.2mmol, p-nitrobenzoic acid 1.5mmol, DMSO 8mL, heating in water bath to 65 ℃, stirring reaction 2h.After reaction finishes, add K
2cO
3solution is removed spent acid, through extraction, washing, filtration, the dry slightly product that to obtain.On product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products is the mixture of the isomers of structural formula 3a and 4a in table 1.Adopt nucleus magnetic resonance and high resolution mass spectrum to characterize product, confirmed the structure of product, measure the ratio of product isomers simultaneously, the results are shown in table 1.
3a：mp?164-166℃;
1H?NMR?(600MHz,?CDCl
3):?δ?2.17?(s,?3H),?2.39?(d,?J=1.8Hz,?3H),?3.39-3.50?(m,?1H),?4.41-4.44?(m,?1H),?5.27-5.30?(t,?J=7.2Hz,?1H),?6.19-6.21?(dd,?J=9.0,?4.2Hz,?1H),?7.02-7.03?(d,?J=8.4Hz,?1H),?7.07-7.08?(d,?J=7.2Hz,?1H),?7.13-7.24?(m,?3H),?7.29-7.30?(d,?J=7.8Hz,?1H),?7.52-7.53?(m,?1H),?7.70-7.71?(d,?J=8.4Hz,?1H),?8.07-8.10?(dt,?J=9.0,?1.8Hz,?1H),?8.15-8.17?(dt,?J=9.0,?1.8Hz,?1H),?8.22-8.24?(d,?J=9.0Hz,?2H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?19.1,?21.4,?46.9,?73.1,?123.5,?125.5,?126.6,?127.0,?128.2,?128.8,?129.4,?129.9,?130.9,?134.9,?135.0,?135.4,?143.7,?150.6,?164.5?ppm;?MS(ESI):?Calcd?for?C
23H
22N
2O
6S+Na?477.1096,?found?477.1093。
Embodiment 2.
In test tube, add in table 2 structural formula as the nitrogen heterocycle propane compound 0.2mmol of 1b, potassium hydroxide 0.08mmol, p-nitrobenzoic acid 0.24mmol, DMSO 1mL, heating in water bath to 45 ℃, stirring reaction 3h.After reaction finishes, add K
2cO
3solution is removed spent acid, through extraction, washing, filtration, the dry slightly product that to obtain.On product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products is the mixture of the isomers of structural formula 3b and 4b in table 2.Adopt nucleus magnetic resonance and high resolution mass spectrum to characterize product, confirmed the structure of product, measure the ratio of product isomers simultaneously, the results are shown in table 2.
3b：mp?140-142℃;
1H?NMR?(600MHz,?CDCl
3):?δ?2.33?(s,?3H),?2.40?(s,?3H),?3.44-3.53?(m,?1H),?4.43-4.54?(m?,1H),?5.19-5.21?(m,?1H),?5.96-5.98?(dd,?J=7.8,?4.2Hz,?1H),?7.05-7.08?(m,?2H),?7.14-7.15?(d,?J=7.8Hz,?2H),?7.20-7.24?(dd,?J=12.0,?8.4Hz,?2H),?7.57-7.58?(d,?J=8.4Hz,?1H),?7.68-7.70?(d,?J=8.4Hz,?1H),?8.06-8.07?(d,?J=9.0Hz,?1H),?8.15-8.17?(d,?J=9.0Hz,?1H),?8.20-8.22?(dd,?J=8.4,?1.8Hz,?1H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?21.2,?21.5,?47.6,?75.7,?123.5,?126.4,?127.0,?129.6,?129.8,?130.9,?133.4,?135.1,?137.0,?139.0,?143.7,?150.6,?163.8?ppm;?MS(ESI):?Calcd?for?C
23H
22N
2O
6S+Na?477.1096,?found?441.1093。
Embodiment 3.
Add table 3 in 50mL Erlenmeyer flask in, structural formula is as the nitrogen heterocycle propane compound 1mmol of 1c, potassium hydroxide 0.4mmol, p-nitrobenzoic acid 1.2mmol, DMSO 5mL, heating in water bath to 45 ℃, stirring reaction 4h.After reaction finishes, add K
2cO
3solution is removed spent acid, through extraction, washing, filtration, the dry slightly product that to obtain.On product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products is the mixture of the isomers of structural formula 3c and 4c in table 3, adopts nucleus magnetic resonance and high resolution mass spectrum to characterize product, has confirmed the structure of product, measures the ratio of product isomers simultaneously, the results are shown in table 3.
3c：mp?146-148℃;?
1H?NMR?(600MHz,?CDCl
3):?δ?2.31?(s,?3H),?3.44-3.49?(m,?1H),?4.42-4.49?(m,?1H),?4.45-4.76?(td,?J=7.8,?1.8Hz,?1H),?6.17-6.19?(d,?J=7.8Hz,?1H),?7.06-7.07?(d,?J=7.8Hz,?1H),?7.09-7.7.14?(m,?2H),?7.17-7.18?(m,?1H),?7.23-7.24?(d,?J=7.8Hz,?1H),?7.27-7.28?(m,?1H),?7.56-7.57?(m,?1H),?7.69-7.70?(dd,?J=7.8,?6.0Hz,?1H),?8.04-8.20?(m,?4H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?21.4,?56.4,?674,?124.4,?125.0,?126.9,?127.2,?128.4,?129.5,?129.9,?130.1,?130.9,?134.6,?137.0,?138.8,?143.7,?150.6,?164.4?ppm。
Embodiment 4.
In test tube, add in table 4 structural formula as the nitrogen heterocycle propane compound 0.2mmol of 1d, cesium hydroxide 0.07mmol, p-nitrobenzoic acid 0.3mmol, DMSO 1.5mL, heating in water bath to 50 ℃, stirring reaction 3h.After reaction finishes, add K
2cO
3solution is removed spent acid, and through extraction, washing, filter, dryly to obtain thick product, on product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products is the mixture of the isomers of structural formula 3d and 4d in table 4, adopts nucleus magnetic resonance and high resolution mass spectrum to characterize product, has confirmed the structure of product, measures the ratio of product isomers simultaneously, the results are shown in table 4.
3d：mp?87-89℃;?
1H?NMR?(600MHz,?CDCl
3):?δ?2.27?(s,?3H),?2.38?(s,?3H),?3.47-3.55?(m,?2H),?3.82?(s,?3H),?3.91?(s,?3H),?4.42-4.43?(m,?2H),?4.66-4.68?(m,?1H),?5.11?(m,?1H),?5.77?(m,?1H),?5.94?(m,?1H),?6.37?(m,?1H),?6.75-6.76?(m,?2H),?6.78-6.87?(m,?2H),?6.93-7.03?(m,?6H),?7.21-7.31?(m,?6H),?7.52-7.54?(d,?J=8.4Hz,?2H),?7.697-7.69?(d,?J=8.4Hz,?2H),?7.76-7.7?(m,?2H),?8.11-8.26?(m,?6H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?21.4,?21.5,?47.6,?55.3,?67.7,?75.6,?112.4,?113.9,?118.5,?118.9,?123.5,?127.0,?129.5,?129.8,?130.1,?130.9,?134.8,?137.0,?137.3,?138.0,?138.3,?143.4,?143.7,?150.6,?159.9,?163.7,?164.5?ppm;?MS(ESI):?Calcd?for?C
23H
22N
2O
7S+Na?493.1045,?found?493.1047。
Embodiment 5.
In test tube, add in table 5 structural formula as the nitrogen heterocycle propane compound 0.2mmol of 1e, sodium hydroxide 0.06mmol, p-nitrobenzoic acid 1mmol, DMSO 1mL, heating in water bath to 40 ℃, stirring reaction 10h, after reaction finishes, adds K
2cO
3solution is removed spent acid, and through extraction, washing, filter, dryly to obtain thick product, on product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products is the mixture of the isomers of structural formula 3e and 4e in table 5, adopts nucleus magnetic resonance and high resolution mass spectrum to characterize product, has confirmed the structure of product, measures the ratio of product isomers simultaneously, the results are shown in table 5.
3e：mp?183-186℃;?
1H?NMR?(600MHz,?CDCl
3):?δ?2.35?(s,?3H),?3.53-3.63?(m,?2H),?5.36-5.38?(t,?J=6.6Hz,?1H),?6.16-6.18?(dd,?J=7.8,?4.8Hz,?1H),?6.92-6.94?(d,?J=7.8Hz,?1H),?7.16-7.17?(d,?J=8.4Hz,?2H),?7.40-7.41?(dd,?J=8.4,?1.8Hz,?1H),?7.48-7.49?(m,?2H),?7.54-7.57?(d,?J=8.4Hz,?1H),?7.65-7.67?(d,?J=8.4Hz,?2H),?7.77-7.81?(m,?3H),?8.17-8.21?(m,?3H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?21.5,?47.6,?75.9,?123.5,?126.1,?126.7,?126.7,?126.9.?127.7,?128.1,?128.9,?129.4,?129.8,?130.9,?133.0,?133.4,?133.7,?135.0,?136.9,?143.7,?150.6,?163.8?ppm;?MS(ESI):?Calcd?for?C
26H
22N
2O
6S+Na?513.1096,?found?513.1095。
Embodiment 6.
Add table 6 in 50mL Erlenmeyer flask in, structural formula is as the nitrogen heterocycle propane compound 1mmol of 1f, sodium hydroxide 0.4mmol, and p-nitrobenzoic acid 2mmol, DMSO 10mL, heating in water bath to 45 ℃, stirring reaction 10h, after reaction finishes, adds K
2cO
3solution is removed spent acid, and through extraction, washing, filter, dryly to obtain thick product, on product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products structure, as structural formula 3f in table 6, adopts proton nmr spectra, carbon spectrum and high resolution mass spectrum to characterize product, has confirmed the structure of product.
3f：mp?142-145℃;?
1H?NMR?(600MHz,?CDCl
3):?δ?1.55-1.58?(m,?1H),?1.71-1.78(m,?4H),?2.08-2.13?(td,?J=13.2,?7.2Hz,?1H),?2.29?(s,?3H),?3.70-3.74?(ddd,?J=13.8,?7.2,?6.0Hz,?1H),?5.13-5.16?(td,?J=7.8,?5.4Hz,?1H),?5.38-5.39?(d,?J=6.0Hz,?1H),?7.15-7.16?(d,?J=7.8Hz,?2H),?7.72-7.74?(d,?J=8.4Hz,?2H),?8.04-8.05?(dt,?J=9.0,?1.8Hz,?2H),?8.24-8.26?(dt,?J=8.4,?2.4Hz,?2H)?ppm;?
13CNMR?(150MHz,?CDCl
3):?δ?20.7,?21.4,?29.5,?31.0,?59.6,?81.0,?123.4,?127.1,?129.6,?130.8,?135.2,?137.4,?143.4,?150.6,?164.4?ppm;?MS(ESI):?Calcd?for?C
19H
20N
2O
6S+Na?427.0940,?found?427.0938。
Embodiment 7.
In test tube, add in table 7 structural formula as the nitrogen heterocycle propane compound 0.2mmol of 1g, potassium hydroxide 0.07mmol, p-nitrobenzoic acid 0.3mmol, DMSO 1.5mL, heating in water bath to 55 ℃, stirring reaction 4h.After reaction finishes, add K
2cO
3solution is removed spent acid, and through extraction, washing, filter, dryly to obtain thick product, on product, silica gel column chromatography column purification obtains open-loop products white solid (eluent is sherwood oil: ethyl acetate=1:4).
Open-loop products structure, as structural formula 4g in table 7, adopts proton nmr spectra, carbon spectrum and high resolution mass spectrum to characterize product, has confirmed the structure of product.The side that p-nitrobenzoic acid attack nitrogen heterocyclic steric hindrance is lower, generates corresponding low steric hindrance product 4g, shows extraordinary regioselectivity
.
4g：mp?116-118℃;?
1H?NMR?(600MHz,?CDCl
3):?δ?0.82-0.85?(t,?J=7.2Hz,?3H),?1.10-1.22?(m,?8H),?1.46-1.53?(m,?2H),?2.36?(s,?3H),?3.60-3.63?(m,?1H),?4.23-4.30?(ddd,?J=16.8,?11.4,?5.4Hz,?2H),?5.18-5.20?(d,?J=8.4Hz,?1H),?7.20-7.22?(d,?J=7.8Hz,?2H),?7.74-7.76?(d,?J=8.4Hz,?2H),?8.11-8.13?(dt,?J=8.4,?2.4Hz,?2H),?8.21-8.23?(dt,?J=8.4,?2.4Hz,?2H)?ppm;?
13C?NMR?(150MHz,?CDCl
3):?δ?13.9,?21.4,?22.4,?25.4,?28.8,?31.5,?32.3,?52.9,?67.3,?123.4,?126.9,?129.7,?130.8,?135.0,?138.5,?143.5,?150.6,?164.5?ppm;?MS(ESI):?Calcd?for?C
22H
28N
2O
6S+Na?471.1566,?found?471.1562。
Claims (4)
1. the nitrogen heterocycle propane compound open-loop method based on p-nitrobenzoic acid, that to take the nitrogen heterocycle propane compound of tosyl group activation be starting raw material, take KOH or NaOH as catalyzer, in dimethyl sulfoxide solvent system, use p-nitrobenzoic acid as nucleophilic reagent, at 40～60 ℃, nitrogen heterocycle propane compound is carried out to ring-opening reaction, wherein, the mol ratio of described p-nitrobenzoic acid and nitrogen heterocycle propane compound is 0.5～5 ︰ 1, and the mole number consumption of alkali metal hydroxide catalyzer is 5～40% of nitrogen heterocycle propane compound mole number;
The nitrogen heterocycle propane compound of described tosyl group activation has following general structure:
In formula, R
1represent H, C
1～C
10alkyl,
,
or
;
Wherein, described R
2represent H, methyl, methoxyl group or halogen;
Or the nitrogen heterocycle propane compound of described tosyl group activation has following general structure:
Wherein, n is 1～7.
2. open-loop method according to claim 1, wherein R
1represent C
1～C
6alkyl,
,
or
;
Wherein, described R
2represent H, methyl, methoxyl group or halogen.
3. open-loop method according to claim 1, wherein n is 3 or 4.
4. according to the open-loop method described in claim 1,2 or 3, the consumption of wherein said dimethyl sulfoxide (DMSO) is 2～10mL/mmol nitrogen heterocycle propane compound.
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Non-Patent Citations (7)
| Title |
|---|
| Hua Mao等.Synthesis of 1-deoxymannojirimycin analogues using N-tosyl and N-nosyl activated aziridines derived from 1-amino-1-deoxyglucitol.《Tetrahedron》.2001,第57卷第6957页. |
| Indium triflate-catalyzed ring opening of aziridines with carboxylic acids;J. S. Yadav等;《Tetrahedron Letters》;20021231;第43卷;第2099-2101页 * |
| J. S. Yadav等.Indium triflate-catalyzed ring opening of aziridines with carboxylic acids.《Tetrahedron Letters》.2002,第43卷第2099-2101页. |
| Ren-Hua Fan，Xue-Long Hou.Tributylphosphine-catalyzed ring-opening reaction of epoxides and aziridines with acetic anhydride.《Tetrahedron Letters》.2003,第44卷第4411-4413页. * |
| Synthesis of 1-deoxymannojirimycin analogues using N-tosyl and N-nosyl activated aziridines derived from 1-amino-1-deoxyglucitol;Hua Mao等;《Tetrahedron》;20011231;第57卷;第6957页 * |
| Unexpected Ring-Opening Reactions of Aziridines with Aldehydes Catalyzed by Nucleophilic Carbenes under Aerobic Conditions;Yan-Kai Liu等;《ORGANIC LETTERS》;20061231;第8卷(第8期);第1521-1524页 * |
| Yan-Kai Liu等.Unexpected Ring-Opening Reactions of Aziridines with Aldehydes Catalyzed by Nucleophilic Carbenes under Aerobic Conditions.《ORGANIC LETTERS》.2006,第8卷(第8期),第1521-1524页. |
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